Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV integrase inhibitor is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide, also known as raltegravir and its pharmaceutically acceptable salts such as raltegravir potassium. Raltegravir is represented by the following structure.

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Raltegravir and its salts can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 03/035077 disclosed N-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides and pharmaceutically acceptable salts thereof. Processes for the preparations of raltegravir and related compounds were disclosed in WO Patent No. 03/035077. According to WO Patent No. 03/035077, raltegravir is prepared by reacting 5-methyl-1,3,4-oxadiazole-2-carboxylic acid with 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide in acetonitrile in presence of triethyl amine and N,N-dimethylformamide.
WO Patent Publication No. 2006/060712 disclosed potassium salt of raltegravir. The publication described the formation of two crystalline forms of raltegravir potassium, which were designated raltegravir potassium salt of crystalline anhydrous Form 1 and crystalline hydrated Form 2. The patent publication noted that attempts to prepare a crystalline sodium salt of raltegravir was unsuccessful, resulting only in amorphous material.
We have discovered that sodium of raltegravir can also be existed as a crystalline product.
Amorphous form and crystalline form H1 of raltegravir potassium were disclosed in co-pending application no. PCT/IN2009/000317.
We have discovered novel salts of raltegravir such as barium, calcium and lithium, and also discovered a process for the preparation of amorphous sodium salt of raltegravir and a process for the preparation of raltegravir potassium crystalline form H1.
Thus, one object of the present invention is to provide a barium salt of raltegravir, process for its preparation and pharmaceutical composition comprising it.
Another object of the present invention is to provide a calcium salt of raltegravir, process for its preparation and pharmaceutical composition comprising it.
Another object of the present invention is to provide a lithium salt of raltegravir, process for its preparation and pharmaceutical composition comprising it.
Another object of the present invention is to provide crystalline sodium salt of raltegravir, process for its preparation and pharmaceutical composition comprising it.
Another object of the present invention is to provide a process for the preparation of amorphous sodium salt of raltegravir.
The salt of the present invention may also serve as intermediate for preparation of raltegravir free base or another salt of raltegravir.
Yet another object of the present invention is to provide a process for the preparation of raltegravir potassium crystalline form H1.